Implantable or insertable medical device resistant to microbial growth and biofilm formation

ABSTRACT

Disclosed are implantable or insertable medical devices that provide resistance to microbial growth on and in the environment of the device and resistance to microbial adhesion and biofilm formation on the device. In particular, the invention discloses implantable or insertable medical devices that comprise at least one biocompatible matrix polymer region, an antimicrobial agent for providing resistance to microbial growth and a microbial adhesion/biofilm synthesis inhibitor for inhibiting the attachment of microbes and the synthesis and accumulation of biofilm on the surface of the medical device. Also disclosed are methods of manufacturing such devices under conditions that substantially prevent preferential partitioning of any of said bioactive agents to a surface of the biocompatible matrix polymer and substantially prevent chemical modification of said bioactive agents

FIELD OF THE INVENTION

[0001] The present invention relates to implantable or insertablemedical devices that provide resistance to microbial growth on and inthe environment of the device and resistance to microbial adhesion andbiofilm formation on the device. In another aspect, the presentinvention relates to methods of manufacturing such implantable orinsertable medical devices, particularly to methods of manufacturingsuch devices that comprise at least one matrix polymer region, anantimicrobial agent for providing resistance to microbial growth and amicrobial adhesion/biofilm synthesis inhibitor for inhibiting theattachment of microbes and the synthesis and accumulation of biofilm onthe surface of the medical device.

BACKGROUND OF THE INVENTION

[0002] Implantable or insertable medical devices such as stents made ofmetallic, polymeric or a composite of metallic and polymeric materialsfrequently occlude due to microbial colonization and adhesion. Thisproblem is particularly prevalent with medical devices that are adaptedto remain implanted for a relatively long-term, i.e., from about 30 daysto about 12 months or longer. Microbes such as bacteria often colonizeon and around the medical device and, upon attaching to surfaces of thedevice, proliferate and form aggregates within a complex matrixconsisting of extracellular polymeric substances, typicallypolysaccharides. The mass of attached microorganisms and the associatedextracellular polymeric substances is commonly referred to as a biofilmor slime. Antimicrobial agents have difficulty penetrating biofilms andkilling and/or inhibiting the proliferation of the microorganisms withinthe biofilm. The colonization of the microbes on and around the deviceand the synthesis of the biofilm barrier eventually result inencrustation, occlusion and failure of the device.

[0003] Previous approaches to minimize this problem have included theuse of low surface energy materials such as Teflon® in implantablemedical devices and the use of surface coatings on such medical devices.Surface coatings have typically comprised single antimicrobials or 1-2antibiotics.

[0004] For example, U.S. Pat. No. 5,853,745 discloses an implantablemedical device having a durable protective coating layer over anantimicrobial coating layer. The coating layers are formed by applyingan antimicrobial coating layer to at least a portion of the surface ofthe medical device, applying a durable coating over the antimicrobialcoating layer, and applying a resilient coating layer over the durablecoating layer.

[0005] U.S. Pat. No. 5,902,283 discloses a non-metallic antimicrobialimpregnated implantable medical device where the antimicrobialcomposition is applied to the device under conditions where theantimicrobial composition permeates the material of the device.

[0006] U.S. Pat. No. 5,772,640 discloses polymeric medical devices thathave been impregnated and/or coated with chlorhexidine and triclosan bydipping or soaking the medical device in a solution of a hydrophobic orhydrophilic polymer containing chlorhexidine and triclosan.

[0007] Published International Application No. WO 99/47595 discloses aplastics material that can be used in certain medical applicationscomprising an acrylic polymer containing 5-50% of a rubbery copolymerand a biocidal compound. The patent also discloses adding antimicrobialagent to the polymer melt by means of a liquid injection system.

[0008] U.S. Pat. No. 5,679,399 discloses membranes that may include oneor more permeable or semipermeable layers containing substances such asbiocides. The layers allow the transmission of environmental fluidsinwardly and the outward dispersion of the biocides. These membranes mayalso include a sealing or coating to entrap agents such as biocidestherein.

[0009] Of the previous approaches, coatings have met with the greatestsuccess because of their proximity to the bacterial environment andhence their active approach to preventing bacterial colonization andattachment. However, this approach has proven inadequate because of thepotential for bacterial resistance to a single narrow spectrum activeagent, because the amount of active agent that can be incorporated intosuch coatings is typically low, and because externally coated tubulardevices release active agents to the environment external to the devicebut not intraluminally.

[0010] In an effort to alleviate the foregoing and other disadvantagesof the prior art, Applicants have developed an implantable or insertablemedical device suitable for long-term implantation and a method formanufacturing such a device, wherein the device provides resistance tomicrobial growth on and around the device and biofilm formation on thedevice. The device of the present invention, therefore, overcomes thedisadvantages associated with the use of coatings as discussed above,and provides a reduced risk of biofilm fouling that eventually resultsin encrustation, occlusion and failure of the device.

SUMMARY OF THE INVENTION

[0011] One aspect of the present invention is directed to an implantablemedical device comprising at least one biocompatible matrix polymerregion and bioactive agents comprising an antimicrobial agent and amicrobial attachment/biofilm synthesis inhibitor. In some preferredembodiments, the medical device comprises multiple distinct matrixpolymer regions. One or more barrier layers at least partially coveringa matrix polymer region may also be provided in preferred embodiments ofthe present invention. Preferred antimicrobial agents include triclosan,chlorhexidine and salts or combinations thereof. Other antimicrobialagents include, but are not limited to nitrofurazone, benzalkoniumchlorides, silver salts and antibiotics suchs as rifampin, gentamycinand minocyclin. Preferred microbial attachment/biofilm synthesisinhibitors include salicylic acid and salts and derivatives thereof. Aradio-opacifying agent is preferably included in a matrix polymerregion, and one or more therapeutic agents may also be present. Thematrix polymer and any barrier layer may preferably comprise abiodegradable or substantially non-biodegradable material such as anethylene vinyl acetate copolymer, copolymers of ethylene with acrylicacid or methacrylic acid; metallocene catalyzed polyethylenes andpolyethylene copolymers, ionomers, elastomeric materials such aselastomeric polyurethanes and polyurethane copolymers, silicones andmixtures thereof. Among medical devices in accordance with the presentinvention are biliary, ureteral and pancreatic stents, stent covers,catheters, venous access devices and devices bridging or providingdrainage between a sterile and non-sterile body environment or betweentwo sterile body environments. Pancreatic stents that release abuffering agent are among preferred pancreatic stents.

[0012] In another aspect, the present invention is directed to a methodof manufacturing an implantable or insertable medical device comprisingproviding one or more biocompatible matrix polymers and bioactive agentscomprising an antimicrobial agent and a microbial attachment/biofilmsynthesis inhibitor; processing the one or more biocompatible matrixpolymers and the bioactive agents under conditions that substantiallyprevent preferential partitioning of any of the bioactive agents to asurface of any of the biocompatible matrix polymers and substantiallyprevent chemical modification of the bioactive agents. Processingpreferably comprises forming a homogenous mixture of the matrix polymerand any bioactive agent and optional radio-opacifying agent and/ortherapeutic agent and shaping the homogeneous mixture into at least aportion of an implantable or insertable medical device. Among preferredshaping processes are included extrusion and coextrusion for multiplelayer structures.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013]FIG. 1 is a simplified schematic representation (perspective view)of a portion of an implantable or insertable medical device inaccordance with an embodiment of the present invention.

[0014]FIG. 2 is a simplified schematic representation (perspective view)of a portion of an implantable or insertable medical device inaccordance with an embodiment of the present invention.

[0015]FIG. 3 is a graph showing bacterial attachment inhibition ontoextruded tubes containing varying amounts of triclosan (TCN) andsalicylic acid (SA).

[0016]FIG. 4 is a graph showing bacterial attachment inhibition ontoextruded tubes containing varying amounts of triclosan (TCN) andsalicylic acid (SA).

[0017]FIG. 5 is a graph showing the zone of bacterial (E. coli ATCC25922) growth inhibition around extruded tubes containing varyingamounts of triclosan (TCN) and salicylic acid (SA).

[0018]FIG. 6 is a graph showing the zone of bacterial (coagulasenegative staph #99) growth inhibition around extruded tubes containingvarying amount of triclosan and salicylic acid (SA).

[0019] As is typically the case with such figures, FIGS. 1 and 2 aresimplified schematic representations presented for purposes ofillustration only, and the actual structures may differ in numerousrespects including the relative scale of the components.

DETAILED DESCRIPTION OF THE INVENTION

[0020] In one aspect, the present invention is directed to animplantable or insertable medical device comprising at least onebiocompatible matrix polymer region, as well as multiple bioactivecomponents, which comprise an antimicrobial agent and a microbialattachment/biofilm synthesis inhibitor.

[0021] The term “biocompatible” as used herein describes a material thatis substantially not toxic to the human body, and that does notsignificantly induce inflammation or other adverse response in bodytissues.

[0022] The term “matrix polymer” as used herein refers to a polymericmaterial that forms at least a portion or region of the implantable orinsertable medical device of the present invention. The matrix polymeris selected to be biocompatible and provide mechanical propertiesconsistent with the intended function and operation of the implantableor insertable medical device. The matrix polymer also serves as arepository in which at least one and, in some preferred embodiments,both the antimicrobial agent and microbial attachment/biofilm synthesisinhibitor are dispersed and/or dissolved. The matrix polymer may alsocontain, as optional components, a radio-opacifying agent and/or one ormore therapeutic agents.

[0023] The term “antimicrobial agent” as used herein means a substancethat kills and/or inhibits the proliferation and/or growth of microbes,particularly bacteria, fungi and yeast. Antimicrobial agents, therefore,include biocidal agents and biostatic agents as well as agents thatpossess both biocidal and biostatic properties. In the context of thepresent invention, the antimicrobial agent kills and/or inhibits theproliferation and/or growth of microbes on and around the surfaces of animplanted medical device.

[0024] The term “microbial attachment/biofilm synthesis inhibitor” asused herein means a substance that inhibits the attachment of microbesonto a surface and the ability of such microbes to synthesize and/oraccumulate biofilm on a surface. In the context of the presentinvention, such a surface includes a surface of an implantable medicaldevice exposed to a physiological environment, such as a physiologicalfluid, that may be conducive to the formation and accumulation ofbiofilm on the surface of the medical device. The microbialattachment/biofilm synthesis inhibitor may also have substantialantimicrobial activity as described herein. Likewise, the antimicrobialagent may also have substantial ability to inhibit microbialattachment/biofilm synthesis.

[0025] By “biofilm” is meant the mass of microorganisms attached to asurface, such as a surface of a medical device, and the associatedextracellular substances produced by one or more of the attachedmicroorganisms. The extracellular substances are typically polymericsubstances and commonly comprise a matrix of complex polysaccharides,proteinaceous substances and glycopeptides. This matrix or biofilm isalso commonly referred to as “glycocalyx.”

[0026] Biofilm formation on the surfaces of implantable or insertablemedical devices adapted for long-term implantation, e.g., from about 30days to 12 months or longer, can result in eventual encrustation andfailure of the device. Further, the proliferation of microbes within thebiofilm can lead to localized infections as well as difficult to treatsystemic infections. The extracellular substances that comprise thebiofilm matrix can act as a barrier that protects and isolates themicroorganisms housed in the biofilm from normal immunological defensemechanisms, such as antibodies and phagocytes, as well as fromantimicrobial agents including surfactants, biocides and antibiotics.The biofilm also facilitates the growth and proliferation of microbeshoused within the biofilm.

[0027] The present invention substantially reduces the risk of biofilmaccumulation on the surfaces of a medical device adapted for long termimplantation, and the resultant likelihood of premature failure of thedevice due to encrustation and occlusion by such biofilm. In somepreferred embodiments of the present invention, the medical device isintended to remain implanted for a relatively long period of from about30 days to about 12 months or longer. However, it is understood that thedevice may be implanted for a period of 30 days or shorter as well.

[0028] The biocompatible matrix polymer of the device of the presentinvention is provided to serve as a repository in which theantimicrobial agent, the microbial attachment/biofilm synthesisinhibitor, or both, are dispersed and/or dissolved. The medical deviceof the present invention will preferably contain at least one matrixpolymer which forms at least a single distinct portion or region of themedical device. Where only a single distinct matrix polymer region isprovided in the medical device, the matrix polymer will preferablycontain both the antimicrobial agent and the microbialattachment/biofilm synthesis inhibitor. However, in other preferredembodiments, the medical device will comprise two or more distinctmatrix polymer regions. Where two or more distinct matrix polymerregions are present in the medical device, it is not necessary that boththe antimicrobial agent and the microbial attachment/biofilm synthesisinhibitor be present in any single one of such multiple matrix polymerregions. Thus, the antimicrobial agent may be present in a first matrixpolymer region and the microbial attachment/biofilm synthesis inhibitormay be present in a second matrix polymer region distinct from the firstmatrix polymer region. However, it is understood that both bioactiveagents may be present in one or all of any distinct matrix polymerregions. Further, as discussed more fully below, where multiple distinctmatrix polymer regions are present, the regions may be separated bybarrier layers that at least partially cover a surface of the matrixpolymer region.

[0029] The amount of the antimicrobial agent present in a matrix polymeris preferably an amount effective to kill and/or inhibit the growth ofmicrobes on and around the implanted medical device. Preferred amountsof the antimicrobial agent present in the matrix polymer range fromabout 0.5% to about 25% by weight of the matrix polymer. Amounts of fromabout 10% to about 25% by weight of the matrix polymer are particularlypreferred.

[0030] The amount of the microbial attachment/biofilm synthesisinhibitor present in a matrix polymer is preferably an amount effectiveto inhibit the attachment of microbes onto and the synthesis and/oraccumulation of biofilm by attached microbes on a surface of theimplanted medical device. Preferred amounts of the antimicrobial agentpresent in the matrix polymer range from about 0.5% to about 25% byweight of the matrix polymer. Amounts of from about 10% to about 25% byweight of the matrix polymer are particularly preferred.

[0031] The amount of antimicrobial agent and/or microbialattachment/biofilm synthesis inhibitor present in a matrix polymer willdepend on, inter alia, on the efficacy of the bioactive agent employed,the length of time during which the medical device is intended to remainimplanted, as well as the rate at which the matrix polymer or barrierlayer releases the bioactive agent in the environment of the implantedmedical device. Thus, a device that is intended to remain implanted fora longer period will generally require a higher percentage of theantimicrobial agent and/or microbial attachment/biofilm synthesisinhibitor. Similarly, a matrix polymer that provides faster release ofthe bioactive agent may require a higher amount of the bioactive agent.The amount of bioactive agent in the matrix polymer may be limited, ofcourse, by the propensity for such bioactive agent to cause undesirablelocalized or systemic toxic reaction and by the potential impairment ofthe mechanical properties necessary for the proper functioning of themedical device.

[0032] In many instances, it is believed that the bioactive agent isreleased, at least in part, from a non-biodegradable matrix polymerregion by a mechanism wherein the matrix polymer imbibes or contactsphysiological fluid. The physiological fluid dissolves or disperses thebioactive agent reposed within the matrix, and the dissolved ordispersed bioactive agent then diffuses outwardly from the matrixpolymer into the physiological environment where the device isimplanted. Matrix polymers need not be permeable to aqueous fluids suchas physiological fluids to provide release of bioactive agent. Matrixpolymers with low permeability to aqueous fluids may adsorb such fluidsat a surface of the polymer. In such matrix polymers, a concentrationgradient is believed to be set up at the surface of the polymer and thebioactive agent is released via diffusion based on its solubility in thesolid polymer relative to its solubility in the fluid or aqueous phase.Where the matrix polymer is biodegradable, similar diffusion processesmay also occur. In a biodegradable matrix polymer, bioactive agent mayalso be released as the biodegradable matrix polymer containing thereposed bioactive agent biodegrades upon contact with the physiologicalenvironment where the device is implanted. Thus, in a biodegradablepolymer, bioactive agent may be released by diffusional processes andupon biodegradation of the polymer matrix.

[0033] The antimicrobial agent present in the matrix polymer can be anypharmaceutically acceptable antimicrobial agent. By “pharmaceuticallyacceptable” as used herein is meant an agent that is approved or capableof being approved by the United States Food and Drug Administration orDepartment of Agriculture as safe and effective for use in humans oranimals when incorporated in or on an implantable or insertable medicaldevice. Preferred antimicrobial agents include, but are not limited to,triclosan, chlorhexidine, nitrofurazone, benzalkonium chlorides, silversalts and antibiotics such as rifampin, gentamycin and minocyclin andcombinations thereof.

[0034] The microbial attachment/biofilm synthesis inhibitor can be anypharmaceutically acceptable agent that inhibits the attachment ofmicrobes onto and the synthesis and/or accumulation of biofilm on asurface of an implantable or insertable medical device. Among preferredmicrobial attachment/biofilm synthesis inhibitors include, but are notlimited to, non-steroidal anti-inflammatory drugs (NSAIDs) and chelatingagents such as EDTA (ethylenediaminetetraacetic acid), EGTA(O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid) andmixtures thereof. Among preferred NSAIDs are salicylic acid and saltsand derivatives thereof. Preferred salts of salicylic acid include, butare not limited to, sodium salicylate and potassium salicylate. Sodiumsalicylate is a particularly preferred salt for use as the microbialattachment/biofilm synthesis inhibitor. Salicylic acid is a particularlypreferred microbial attachment/biofilm synthesis inhibitor.

[0035] Some preferred combinations of antimicrobial agent and microbialattachment/biofilm synthesis inhibitors present in a medical device inaccordance with the present invention comprise triclosan and/orchlorhexidine in combination with salicylic acid or a salt thereof suchas sodium salicylate. The combination of triclosan and salicylic acid ora salt thereof is particularly preferred.

[0036] The presence of both an antimicrobial agent and a microbialattachment/biofilm synthesis inhibitor in a medical device in accordancewith the present invention provides distinct advantages over the use of,for example, only an antimicrobial agent. The use of such a dualmechanism for preventing microbial colonization and attachment isbelieved to have a synergistic effect. The synergy is related to thedifferent mechanism of action of each of the bioactive agents. Theantimicrobial agent not only kills a large percentage of microbesapproaching a surface of the device, it also reduces the burden ofmicrobes upon which the microbial attachment/biofilm synthesis inhibitormust act. Moreover, microbes that have attached to a surface produce aprotective biofilm barrier after attachment. This biofilm barrierprevents or reduces the ability of antimicrobial agents from reachingthe microbes. The antimicrobial agent is thereby rendered substantiallyless effective upon formation of the biofilm barrier. Therefore, ifmicrobial attachment is prevented, biofilm synthesis is inhibited andthe antimicrobial agent is rendered more effective.

[0037] The matrix polymer used in the implantable or insertable medicaldevice of the present invention may be any biocompatible polymersuitable for use in implantable or insertable medical devices. Thematrix polymer may be substantially non-biodegradable or biodegradable.

[0038] Preferred substantially non-biodegradable biocompatible matrixpolymers include thermoplastic and elastomeric polymeric materials.Polyolefins such as metallocene catalyzed polyethylenes, polypropylenes,and polybutylenes and copolymers thereof; vinyl aromatic polymers suchas polystyrene; vinyl aromatic copolymers such as styrene-isobutylenecopolymers and butadiene-styrene copolymers; ethylenic copolymers suchas ethylene vinyl acetate (EVA), ethylene-methacrylic acid andethylene-acrylic acid copolymers where some of the acid groups have beenneutralized with either zinc or sodium ions (commonly known asionomers); polyacetals; chloropolymers such as polyvinylchloride (PVC);fluoropolymers such as polytetrafluoroethylene (PTFE); polyesters suchas polyethyleneterephthalate (PET); polyester-ethers; polyamides such asnylon 6 and nylon 6,6; polyamide ethers; polyethers; elastomers such aselastomeric polyurethanes and polyurethane copolymers; silicones;polycarbonates; and mixtures and block or random copolymers of any ofthe foregoing are non-limiting examples of non-biodegradablebiocompatible matrix polymers useful for manufacturing the medicaldevices of the present invention.

[0039] Among particularly preferred non-biodegradable polymericmaterials are polyolefins, ethylenic copolymers including ethylene vinylacetate copolymers (EVA) and copolymers of ethylene with acrylic acid ormethacrylic acid; elastomeric polyurethanes and polyurethane copolymers;metallocene catalyzed polyethylene (mPE), mPE copolymers, ionomers, andmixtures and copolymers thereof; and vinyl aromatic polymers andcopolymers. Among preferred vinyl aromatic copolymers are includedcopolymers of polyisobutylene with polystyrene or polymethylstyrene,even more preferably polystyrene-polyisobutylene-polystyrene triblockcopolymers. These polymers are described, for example, in U.S. Pat. No.5,741,331, U.S. Pat. No. 4,946,899 and U.S. Ser. No. 09/734,639, each ofwhich is hereby incorporated by reference in its entirety. Ethylenevinyl acetate having a vinyl acetate content of from about 19% to about28% is an especially preferred non-biodegradable material. EVAcopolymers having a lower vinyl acetate content of from about 3% toabout 15% are also useful in particular embodiments of the presentinvention as are EVA copolymers having a vinyl acetate content as highas about 40%. These relatively higher vinyl acetate content copolymersmay be beneficial in offsetting stiffness from coextruded barrierlayers. Among preferred elastomeric polyurethanes are block and randomcopolymers that are polyether based, polyester based, polycarbonatebased, aliphatic based, aromatic based and mixtures thereof.Commercially available polyurethane copolymers include, but are notlimited to, Carbothane®, Tecoflex®, Tecothane®, Tecophilic®, Tecoplast®,Pellethane®, Chronothane® and Chronoflex®. Other preferred elastomersinclude polyester-ethers, polyamide-ethers and silicone.

[0040] Among preferred biodegradable matrix polymers are included, butnot limited to, polylactic acid, polyglycolic acid and copolymers andmixtures thereof such as poly(L-lactide) (PLLA), poly(D,L-lactide)(PLA); polyglycolic acid [polyglycolide (PGA)],poly(L-lactide-co-D,L-lactide) (PLLA/PLA), poly(L-lactide-co-glycolide)(PLLA/PGA), poly(D, L-lactide-co-glycolide) (PLA/PGA),poly(glycolide-cotrimethylene carbonate) (PGA/PTMC),poly(D,L-lactide-co-caprolactone) (PLA/PCL),poly(glycolide-co-caprolactone) (PGA/PCL); polyethylene oxide (PEO),polydioxanone (PDS), polypropylene fumarate, poly(ethylglutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethylglutamate), polycaprolactone (PCL), polycaprolactone co-butylacrylate,polyhydroxybutyrate (PHBT) and copolymers of polyhydroxybutyrate,poly(phosphazene), poly(phosphate ester), poly(amino acid) andpoly(hydroxy butyrate), polydepsipeptides, maleic anhydride copolymers,polyphosphazenes, polyiminocarbonates, poly[(97.5% dimethyl-trimethylenecarbonate)-co-(2.5% trimethylene carbonate)], cyanoacrylate,polyethylene oxide, hydroxypropylmethylcellulose, polysaccharides suchas hyaluronic acid, chitosan and regenerate cellulose, and proteins suchas gelatin and collagen, and mixtures and copolymers thereof, amongothers.

[0041] Particularly preferred biodegradable polymers comprise polylacticacid, polyglycolic acid and copolymers and mixtures thereof.

[0042] The medical device of the present invention may also contain aradio-opacifying agent within its structure. For example, theradio-opacifying agent may be present in or on any of the matrix polymerregions or in or on an optional barrier layer that at least partiallycovers a surface of a matrix polymer region. Barrier layers aredescribed more fully below. The radio-opacifying agent facilitatesviewing of the medical device during insertion of the device and at anypoint while the device is implanted. A radio-opacifying agent typicallyfunctions by scattering x-rays. The areas of the medical device thatscatter the x-rays are detectable on a radiograph. Amongradio-opacifying agents useful in the medical device of the presentinvention are included, but not limited to, bismuth subcarbonate,bismuth oxychloride, bismuth trioxide, barium sulfate, tungsten andmixtures thereof. Where present, the radio-opacifying agent ispreferably present in an amount of from about 0.5% to about 90%, morepreferably from about 10% to about 90% by weight, of the matrix polymer.A particularly preferred amount of radio-opacifying agent is from about10 to about 40% by weight of the matrix polymer.

[0043] The medical device of the present invention may also contain oneor more therapeutic agents within its structure. For example, anytherapeutic agent may be present in or on any of the matrix polymerregions or in or on any optional barrier layer that at least partiallycovers a surface of a matrix polymer region. The therapeutic agent maybe any pharmaceutically acceptable agent. A therapeutic agent includesgenetic therapeutic agents, non-genetic therapeutic agents and cells.

[0044] Exemplary non-genetic therapeutic agents include: (a)anti-thrombotic agents such as heparin, heparin derivatives, urokinase,and PPack (dextrophenylalanine proline arginine chloromethylketone); (b)steroidal and non-steroidal anti-inflammatory agents (NSAIDs) such asdexamethasone, prednisolone, corticosterone, hydrocortisone andbudesonide estrogen, sulfasalazine and mesalamine, salicylic acid andsalts and derivatives thereof, ibuprofen, naproxen, sulindac,diclofenac, piroxicam, ketoprofen, diflunisal, nabumetone, etodolac,oxaprozin and indomethacin;

[0045] (c) chemotherapeutic agents such asantineoplastic/antiproliferative/antimitotic agents includingpaclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,epothilones, endostatin, angiostatin, doxorubicin, methotrexate,angiopeptin, monoclonal antibodies capable of blocking smooth musclecell proliferation, and thymidine kinase inhibitors; (d) anestheticagents such as lidocaine, bupivacaine and ropivacaine; (e)anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGDpeptide-containing compound, heparin, hirudin, antithrombin compounds,platelet receptor antagonists, antithrombin antibodies, anti-plateletreceptor antibodies, aspirin, prostaglandin inhibitors, plateletinhibitors and tick antiplatelet peptides; (f) vascular cell growthpromoters such as growth factors, transcriptional activators, andtranslational promoters; (g) vascular cell growth inhibitors such asgrowth factor inhibitors, growth factor receptor antagonists,transcriptional repressors, translational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxin, bifunctional molecules consisting of an antibody and acytotoxin; (h) protein kinase and tyrosine kinase inhibitors (e.g.,tyrphostins, genistein, quinoxalines); (i) prostacyclin analogs; (j)cholesterol-lowering agents; (k) angiopoietins; (l) antimicrobial agentssuch as triclosan, cephalosporins, β-lactams, aminoglycosides andnitrofurantoin; (m) chemotherapeutic agents such as cytotoxic agents,cytostatic agents and cell proliferation affectors; (n) vasodilatingagents; and (o)agents that interfere with endogenous vascoactivemechanisms.

[0046] Exemplary genetic therapeutic agents include anti-sense DNA andRNA as well as DNA coding for: (a) anti-sense RNA, (b) tRNA or rRNA toreplace defective or deficient endogenous molecules, (c) angiogenicfactors including growth factors such as acidic and basic fibroblastgrowth factors, vascular endothelial growth factor, epidermal growthfactor, transforming growth factor α and β, platelet-derived endothelialgrowth factor, platelet-derived growth factor, tumor necrosis factor a,hepatocyte growth factor and insulin-like growth factor, (d) cell cycleinhibitors including CD inhibitors, and (e) thymidine kinase (“TK”) andother agents useful for interfering with cell proliferation. Also ofinterest is DNA encoding for the family of bone morphogenic proteins(“BMP's”), including BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7(OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15,and BMP-16. Currently preferred BMP's are any of BMP-2, BMP-3, BMP-4,BMP-5, BMP-6 and BMP-7. These dimeric proteins can be provided ashomodimers, heterodimers, or combinations thereof, alone or togetherwith other molecules. Alternatively, or in addition, molecules capableof inducing an upstream or downstream effect of a BMP can be provided.Such molecules include any of the “hedgehog” proteins, or the DNA'sencoding them.

[0047] Vectors of interest for delivery of genetic therapeutic agentsinclude (a) plasmids, (b) viral vectors such as adenovirus,adenoassociated virus and lentivirus, and (c) non-viral vectors such aslipids, liposomes and cationic lipids.

[0048] Cells include cells of human origin (autologous or allogeneic),including stem cells, or from an animal source (xenogeneic), which canbe genetically engineered if desired to deliver proteins of interest.

[0049] Among preferred therapeutic agents that may optionally be presentin a medical device of the present invention include, but are notlimited to, steroidal and non-steroidal anti-inflammatory agents(NSAIDs) and chemotherapeutic agents such asantineoplastic/antiproliferative/anti-mitotic agents, cytotoxic agents,cytostatic agents and cell proliferation affectors. Examples ofchemotherapeutic agents include cisplatin, methotrexate, doxorubicin,paclitaxel and docetaxel. Examples of steroidal anti-inflammatory agentsinclude dexamethasone, hydrocortisone and prednisone.

[0050] The therapeutic agent may be applied onto or into the device orany portion thereof (the matrix polymer region or any optional barrierlayer, for example) by contacting the device or portion thereof with asolution or suspension of the therapeutic agent, for example byspraying, dipping, and so forth, followed by evaporating the solvent orcarrier liquid. The drug may also be incorporated during the processingand/or shaping of any of the matrix polymers and/or optional polymericbarrier layers used to form the medical device of the present inventionprovided that the drug is stable at the conditions (e.g., temperatureand pressure) required during such processing and/or shaping.

[0051] The amount of the therapeutic agent will be a therapeuticallyeffective amount. As with the antimicrobial agent and microbialattachment/biofilm synthesis inhibitor, the amount of any therapeuticagent present in a medical device will depend, inter alia, on theparticular therapeutic agent, the length of time during which themedical device is intended to remain implanted, and the rate at whichthe therapeutic agent is released from the matrix polymer and/or barrierlayer. The amount of the therapeutic agent may be limited by thepropensity of such agent to cause an undesirable localized or systemictoxic reaction and by the impairment of mechanical properties necessaryfor proper functioning of the device.

[0052] The medical device of the present invention may comprise amultilayer structure comprising from 2 to about 50 distinct layers, morepreferably from about 2 to about 20 layers formed by coextrusion asdescribed more fully below. Preferred multilayer structures may havefrom about 2 to about 7 distinct layers. Particularly preferredmultilayer structures have from about 3 to about 7 layers, with a 3layer construction being especially preferred. As noted above, themedical device comprises one or more matrix polymer regions. The medicaldevice can also comprise one or more barrier regions as well. Hence, ina multilayer construction, one or more of the distinct layers may be abarrier layer that least partially covers one or more matrix polymerlayers. Thus, the medical device of the present invention may compriseone or more layers comprising one or more distinct matrix polymer layersand, if desired, one or more barrier layers.

[0053] Multilayer structures of the present invention need not comprisea barrier layer. For example, a medical device in accordance with thepresent invention may comprise a two-layer structure comprising a firstmatrix polymer layer containing the bioactive agents andradio-opacifying agent and a second layer on an external surface of thefirst matrix polymer layer wherein the second layer provides lubricity.Such a lubricious layer may be desirable, for example, to facilitateinsertion and implantation of the medical device.

[0054] It is understood that the medical device of the present inventionis not limited to a multiple layer structure and, indeed, a single layerstructure such as an annular tube comprising a matrix polymer, anantimicrobial agent, a microbial attachment/biofilm synthesis inhibitorand an optional radio-opacifying agent, is within the scope of thepresent invention.

[0055] Medical devices in accordance with the present invention havingmultiple layer structures may provide certain advantages relative tosingle layer devices, however. For example, a barrier layer can beprovided to control the rate of release of bioactive material ortherapeutic agent from an adjacent layer, such a matrix polymer layer.The barrier layer, as described more filly below, may also beadvantageous in substantially reducing the partitioning of a bioactiveagent to the surface of a matrix polymer layer during processing.Multiple layers, such as distinct matrix polymer layers, may also act asreservoirs for different bioactive agents and/or combinations of abioactive agent, a radio-opaque material and a therapeutic agent. Hence,the use of multiple layers may be advantageous in providing differentrelease profiles of different bioactive agents and/or therapeuticagents. For example, the release characteristics of a particularbioactive and/or therapeutic agent may depend on its ability to diffusefrom a particular matrix polymer. Thus, different compositions of matrixpolymer and bioactive and/or therapeutic agent may provide differentrelease characteristics therefrom. Some compositions may result inrelatively fast release while others may result in a relatively slowerrelease profile. By appropriate selection and arrangement of distinctlayers of matrix polymer containing bioactive and/or therapeutic agents,the release profile of the different bioactive and/or therapeutic agentfrom the device may be optimized for a particular application.

[0056] For example, in one embodiment of the present invention adaptedto provide controlled release of a bioactive and any optionaltherapeutic agents, there is provided a multilayer structure comprisinga first annular layer comprising a biocompatible matrix polymer, anantimicrobial agent, a microbial attachment/biofilm synthesis inhibitorand, optionally, a therapeutic agent. First and second barrier layers(also annular in shape) are disposed on the exterior and interiorsurfaces, respectively, of the first annular layer. The first and secondbarrier layers that enclose the first annular layer are typically lesspermeable than the biocompatible matrix polymer and, thereby, controlthe rate of diffusion of the bioactive and optional therapeutic agentsfrom the device to the external environment.

[0057] A simplified schematic representation of this embodiment of thepresent invention is depicted in FIG. 1. Implantable or insertablemedical device 100 in accordance with this embodiment of the presentinvention comprises an annular first matrix polymer region 101; anannular first polymeric barrier layer 111 at least partially covering aninterior surface of first matrix polymer region 101 and, an annularsecond polymeric barrier layer 112 at least partially covering anexterior surface of first matrix polymer region 101. Annular first andsecond polymeric barrier layers 111 and 112, respectively, may have thesame or a different composition.

[0058] The barrier layers preferably comprise polymeric materials. Anyof the non-biodegradable and biodegradable polymers describedhereinabove in relation to the matrix polymer may also form a barrierlayer. Preferred barrier layer polymers include, but are not limited to,ethylenic copolymers such as ethylene vinyl acetate and copolymers ofethylene with acrylic or methacrylic acid, elastomers includingelastomeric polyurethanes and block and random copolymers thereof,metallocene catalyzed polyethylene (mPE) and mPE copolymers, ionomers,silicones and mixtures thereof. Metallocene catalyzed polyethylenes andmPE copolymers, such as copolymers of ethylene with octene, and ionomersand may be particularly preferred polymeric barrier layer materials tocontrol partitioning of any bioactive agent such as salicylic acid orsodium salicylate to the surface of the matrix polymer during processingand to provide controlled release of active agents from the matrixpolymer.

[0059] A barrier layer and any contacting matrix polymer layer or regionwill preferably comprise different polymeric materials. Differentpolymeric materials will generally provide different rates of diffusionor release of bioactive agent. Thus, less permeable barrier layers maybe provided to control the rate of release of a bioactive agent from acontacting matrix polymer region which may be more permeable todiffusion of a bioactive agent. For example, where an EVA copolymerhaving a vinyl acetate content of from about 19% to about 28% is used asthe matrix polymer, an EVA copolymer having a lower vinyl acetatecontent of from about 3% to about 15% may be useful to form thecontacting barrier layer. Lower vinyl acetate content EVA copolymers areuseful as barrier layers because of their lower permeability, henceability to release bioactive agent more slowly than higher vinyl acetatecontent copolymers. The relative rigidity or stiffness of such lowervinyl acetate content barrier layers may be offset somewhat by the useof higher vinyl acetate content matrix polymer layers or regions.

[0060] While two barrier layers are provided in medical device 100depicted in FIG. 1, it is understood that a medical device of thepresent invention may comprise an annular matrix polymer region providedwith no barrier layer, or with a single barrier layer at least partiallycovering an exterior or interior surface of the annular matrix polymerregion. It is also understood that while annular matrix polymer regionsand annular barrier layers may be preferred in some embodiments of thepresent invention, neither any matrix polymer region nor any barrierlayer need be annular.

[0061] In the medical device depicted in FIG. 1, and the above-describedand other modifications thereof in accordance with the presentinvention, the first matrix polymer region preferably comprises abiocompatible matrix polymer as described herein, an antimicrobialagent, a microbial attachment biofilm synthesis inhibitor and, asoptional components, one or more of a radio-opacifying agent and atherapeutic agent.

[0062] Another embodiment of the present invention comprising amulti-layer structure will now be described. In this embodiment, thedevice is designed to provide slower release of a bioactive and/ortherapeutic agent from a first matrix polymer composition relative torelease of a bioactive and/or therapeutic agent from a second matrixpolymer composition. In this embodiment, there is provided an annularlayer of the first matrix polymer composition between distinct annularlayers of the second matrix polymer composition. In such a multilayerconfiguration, each surface of the second matrix polymer compositionthat would otherwise be exposed to the external environment is providedwith a barrier layer. Similarly, barrier layers are provided between theannular layer of the first matrix polymer composition and the annularlayers of the second matrix polymer composition. The resulting structurecomprises seven layers, three of which form distinct matrix polymerregions and four of which form barrier layers covering at least aportion of one or more surfaces of the matrix polymer regions. In thisconfiguration, the bioactive and/or therapeutic agent from the annularlayer comprising the first matrix polymer composition would have todiffuse through its own barrier layer, into and through an annular layercomprising the second matrix polymer composition and through anotherbarrier layer before reaching the external environment. This multi-layerconfiguration provides a slower release of bioactive and/or therapeuticagent from the annular layer of the first matrix polymer compositionrelative to the rate of release of bioactive and/or therapeutic agentfrom the annular layer of the second matrix polymer composition.

[0063] A simplified schematic representation of this embodiment of thepresent invention is depicted in FIG. 2. Implantable or insertablemedical device 200 in accordance with this embodiment of the presentinvention comprises annular first matrix polymer region 201; annularfirst polymeric barrier layer 211 at least partially covering aninterior surface of first matrix polymer region 201; annular secondpolymeric barrier layer 212 at least partially covering an exteriorsurface of first matrix polymer region 201; annular second matrixpolymer region 202 at least partially covering an exterior surface ofannular second polymeric barrier layer 212; annular third polymericbarrier layer 213 at least partially covering an exterior surface ofannular second matrix polymer region 202; annular third matrix polymerregion 203 disposed on an interior surface of annular first polymericbarrier layer 211; and annular fourth polymer barrier layer 214 at leastpartially covering an interior surface of annular third matrix polymerregion 203.

[0064] Annular first, second, and third matrix polymer regions 201, 202and 203, respectively, may have the same or different compositions. In apreferred embodiment, annular second and third matrix polymer regions202 and 203, respectively, have the same composition which is differentfrom the composition of annular first matrix polymer region 201. In thispreferred embodiment, it is also preferred that annular first and secondpolymeric barrier layers 211 and 212, respectively, have the samecomposition and annular third and fourth polymer barrier layers 213 and214, respectively, have the same composition. In this embodiment, it isparticularly preferred that the annular first and second polymericbarrier layers 211 and 212, respectively, have a composition differentfrom that of the annular third and fourth polymeric barrier layers, 213and 214, respectively. However, more broadly, annular first, second,third and fourth polymeric barrier layers 211, 212, 213 and 214,respectively, may have the same or different compositions. Similarly,annular first, second and third matrix polymer regions 201, 202 and 203,respectively may have the same or different compositions.

[0065] Another embodiment of the present invention may also be describedwith reference to FIG. 2. In this embodiment, the medical device has twomatrix polymer regions and three polymeric barrier layers. Thisembodiment of the present invention may be envisioned by removing, fromthe medical device depicted in FIG. 2, annular third matrix polymerregion 203 and annular fourth polymer barrier layer 214, therebyresulting in a five layer structure comprising two distinct matrixpolymer regions (201, 202) and three polymeric barrier layers (211, 212,213) at least partially covering one or more surfaces of the distinctmatrix polymer regions.

[0066] It is understood that other configurations of barrier layers andmatrix polymer regions are within the scope of the present invention.For example, again with reference to FIG. 2, a five layer structurewithin the scope of the present invention may be envisioned by removingannular third and fourth polymeric barrier layers, 213 and 214,respectively. In this embodiment, the resulting five layer structurewill comprise three distinct matrix polymer regions (201, 202, 203)separated from each other by two barrier layers (211, 212) disposed oninner and outer surfaces of annular first matrix polymer region 201.

[0067] In the medical device depicted in FIG. 2, and the above-describedand other modifications thereof in accordance with the presentinvention, any of the first, second and optional third matrix polymerregions preferably comprises a biocompatible matrix polymer as describedherein and either or both of an antimicrobial agent and a microbialattachment biofilm synthesis inhibitor and, as optional components, oneor more of a radio-opacifying agent and a therapeutic agent.

[0068] The present invention is not to be construed as limited in anyway by the simplified schematic representations of the embodiments ofthe present invention as depicted in FIG. 1 or 2. Thus, a medical devicein accordance with the present invention can be a single layer ormultilayer construction; may have one or multiple matrix polymer regionsand may have none, one or multiple barrier layers. Moreover, neither anymatrix polymer region nor any barrier layer need be annular as depictedin the Figures. Further, where a barrier or other layer is provided inaddition to a matrix polymer layer, any of a bioactive agent, aradio-opacifying agent and a therapeutic agent may be provided in or onsuch barrier or other layer.

[0069] Further optimization of release profiles can be obtained byproviding a multilayer structure having both biodegradable andsubstantially non-biodegradable layers. Matrix polymer layers havingdifferent rates of biodegradation can, for example, provide differentrelease profiles of bioactive and/or therapeutic agents. By appropriateselection and placement of such biodegradable layers, release profilescan be optimized based on the desired time-dependent requirements forrelease of such bioactive and/or therapeutic agents.

[0070] Multiple layers may also be provided to act as barrier layers toseparate, at least temporarily, otherwise incompatible polymers,bioactive agents, therapeutic agents and radio-opacifying agents. Forexample, such materials or agents may not be compatible with anothersuch material or agent under the processing conditions employed tomanufacture the medical device. As a specific example, an antimicrobialagent such as chlorhexidine may react with a microbialattachment/biofilm synthesis inhibitor such as salicylic acid when mixedwith an EVA copolymer under certain conditions in a twin screw extruder.The resultant chemical modification of the compounds may render themineffective for their intended purpose. As another example, aradio-opacifying agent such as bismuth subcarbonate may react with anantimicrobial agent such as salicylic acid under certain processingconditions necessary for a particular matrix polymer.

[0071] The use of a barrier layer is also advantageous in substantiallyreducing or preventing the preferential partitioning of a bioactiveagent to the surface of a medical device during or subsequent toprocessing. For example, a microbial attachment/biofilm synthesisinhibitor such as salicylic acid may preferentially partition to thesurface of a matrix polymer such as an EVA copolymer during orsubsequent to some of the processing steps involved in formation of themedical device. This preferential partitioning may be referred to as“blooming.” It is believed that blooming may result, at least in part,when the bioactive agent has limited solubility in the polymer,particularly as it is cooled after processing. Also, a bioactive agentthat has greater solubility in water than in a matrix polymer may bemore susceptible to blooming during processing of the matrix polymer andbioactive agent. It may, therefore, be desirable to control moisturecontent during processing of the bioactive agent and matrix polymer toprevent blooming of bioactive agent. In any event, blooming may resultin the appearance of crystals of the bioactive agent, such as salicylicacid, on the surface of the device within hours after processing.

[0072] In one embodiment of the present invention adapted tosubstantially reduce or prevent blooming, there is provided a multilayerstructure comprising a first annular layer comprising a biocompatiblematrix polymer, an antimicrobial agent, a microbial attachment/biofilmsynthesis inhibitor; and annular first and second barrier layers on theexterior and interior surfaces, respectively, of the first annular layer(as optional components, a radio-opacifying agent and/or a therapeuticagent may also be added to one or more of the layers). Blooming orpartitioning of a bioactive agent to a surface of the device can beeffectively controlled by providing the first and second annular barrierlayers in this embodiment. A medical device in accordance with thisembodiment comprising a three layer structure adapted to substantiallyreduce blooming may have a stucture similar to that shown in FIG. 1,described hereinabove.

[0073] In another aspect, the present invention is directed to a methodof manufacturing an implantable or insertable medical device comprising(a) providing one or more biocompatible matrix polymers, one or moreantimicrobial agents and one or more microbial attachment/biofilmsynthesis inhibitor and, optionally, one or more of a radio-opacifyingagent and/or a therapeutic agent; (b) processing the one or morebiocompatible matrix polymers and the bioactive agents, preferably underconditions that substantially prevent preferential partitioning of anyof the bioactive agents to a surface of any of the biocompatible matrixpolymers and that substantially prevent chemical modification of thebioactive agents.

[0074] Processing typically comprises mixing or compounding the matrixpolymer, bioactive agents and optional radio-opacifying and/ortherapeutic agents to form a homogeneous mixture thereof and shaping thehomogenous mixture into a matrix polymer region of an implantable orinsertable medical device. The mixing and shaping operations, asdescribed more fully below, may be performed using any of theconventional devices known in the art for such purposes. In thefollowing description, the one or more bioactive agents and optionalradio-opacifying and/or therapeutic agents will, at times, becollectively referred to as “additives” or “agents.”

[0075] During processing, there exists the potential for one of more ofthe polymer matrix material, bioactive agents and optionalradio-opacifying and/or therapeutic agents to become chemically modifiedby cross-reacting with one another. These undesirable cross-reactionsmay result from the incompatibility or instability of these agents atthe elevated temperatures typically involved during the processing. Itis also believed that excessive moisture content during processing mayfacilitate chemical modification of the agents.

[0076] Excessive moisture content can also facilitate blooming of abioactive agent to a surface of a matrix polymer. Other processingconditions can also result, as discussed hereinabove, in blooming of oneor more of the bioactive agents to the surface of a matrix polymerduring and/or subsequent to processing.

[0077] Hence, processing is preferably performed under conditions thatsubstantially prevent preferential partitioning of any of the agents andsubstantially prevent chemical modification of the agents. It isunderstood that some partitioning and chemical modification may beunavoidable during processing. Therefore, by “substantially prevent” ismeant that no more than about 25% by weight, preferably less than about10% by weight (based on the weight of the matrix polymer composition),of any bioactive agent is preferentially partitioned to a surface of amatrix polymer and/or chemically modified during processing.

[0078] Among the processing conditions that may be controlled duringprocessing to substantially reduce the risk of partitioning and/orchemical modification are the temperature, moisture content, appliedshear rate and residence time of the mixture of matrix polymer,bioactive agents, and optional radio-opacifying and/or therapeuticagents in a processing device.

[0079] Mixing or compounding a matrix polymer with one or more of thebioactive agents and optional radio-opacifying and/or therapeutic agentsto form a homogeneous mixture thereof may be performed with any deviceknown in the art and conventionally used for mixing polymeric materialswith additives. Where thermoplastic materials are employed, a polymermelt is formed by heating the various agents, which can then be mixed toform a homogenous mixture. A common way of doing so is to applymechanical shear to a mixture of the matrix polymer and additives.Devices in which the matrix polymer and additives may be mixed in thisfashion include, but are not limited to, devices such as a single screwextruder, a twin screw extruder, a banbury mixer, a high-speed mixer,and a ross kettle.

[0080] Mixing may also be achieved by dissolving the matrix polymer withone or more of the bioactive agents and optional radio-opacifying and/ortherapeutic agents in a solvent system or forming a liquid dispersion ofthe same.

[0081] Any of the matrix polymer and/or additives may be precompoundedor individually premixed to facilitate subsequent processing. Forexample, a radio-opacifying agent may be precompounded with a matrixpolymer and then mixed with any bioactive agent. Alternatively, theradio-opacifying agent such as bismuth subcarbonate may be preblendedwith any bioactive agent in a device such as a v-mixer with anintensifier bar before being mixed with the matrix polymer.

[0082] In some preferred embodiments, a homogenous mixture of the matrixpolymer and additives is produced using a twin screw extruder, such as atwin screw extruder with a low-shear profile design. Barrel temperature,screw speed and throughput are typically controlled to preventpartitioning and chemical modification as discussed hereinabove.

[0083] The conditions necessary to achieve a homogenous mixture of thematrix polymer and additives during compounding will depend, to someextent, on the specific matrix polymer as well as the type of mixingdevice used. For example, different matrix polymers will typicallysoften into a melt to facilitate mixing at different temperatures. It isgenerally preferred to mix the matrix polymer and additives at atemperature from about 60° C. to about 140° C., more preferably fromabout 70° C. to about 100° C., most preferably from about 80° C. toabout 90° C. These temperature ranges have been found to result information of a homogenous mixture of the matrix polymer and additives,while substantially preventing partitioning and chemical modification.Some combinations of matrix polymer and additive can be processed at alower temperature than might otherwise be expected to result inhomogeneous mixing. For example, while

[0084] 70° C. may be a relatively low temperature for processing an EVAcopolymer and an additive, an antimicrobial agent such as triclosan,which melts at a temperature of around 50° C., may act as a plasticizerfor the EVA, facilitating use of a lower temperature of about 70° C. Theability to process the EVA at a lower temperature by virtue of anadditive acting as a plasticizer advantageously reduces the risk ofchemical modification of the additives if a higher temperature wereotherwise required. Higher temperatures may be employed, however, duringsubsequent shaping of the homogenous mixture into a portion of a medicaldevice as described herein. For example, higher temperatures may benecessary in localized portions of a coextrusion device used to apply abarrier layer onto one or more surfaces of the matrix polymer. However,the time at which the higher temperatures are encountered by the mixtureare generally kept to a mininum.

[0085] The mixture of matrix polymer and additives can be shaped into atleast a portion of a medical device in accordance with the presentinvention by means of any process conventionally used to shape polymericmaterials such as thermoplastic and elastomeric materials. Among suchshaping processes are included, but not limited to, extrusion includingcoextrusion, molding, calendaring, casting and solvent coating. Amongpreferred shaping processes are extrusion and coextrusion processes.

[0086] Coextrusion is a particularly preferred shaping process whereinat least a portion of a medical device in accordance with the presentinvention is a multilayer structure, for example, comprising one or moredistinct matrix polymer regions and one or more barrier layers at leastpartially covering a surface of a matrix polymer region. Among preferredcoextruded multilayer structures are those having 3 to 7 distinct layersas described hereinabove. Especially preferred coextruded structures arethose in which each of the matrix polymer regions and contactingbarriers layers have annular shapes. For example, a three layerstructure may be formed by coextruding annular polymeric barrier layerswith an annular matrix polymer region such that the polymeric barrierlayers at least partially cover interior and exterior surfaces of thematrix polymer region. Two, five, and seven layer constructions asdescribed herein may be similarly formed by coextrusion, as can anymultilayer construction having from 2 to about 50 layers. It is alsounderstood that a medical device of the present invention may be formedby extruding a single annular matrix polymer containing bioactiveagents, an optional radio-opacifying agent and an optional therapeuticagent. Multi-layer structures can also be formed by other processing andshaping techniques such as laminar injection molding (LIM) technology.

[0087] The temperatures used for shaping the matrix polymer and anybarrier layers will, of course, depend on the particular materials usedand the shaping device employed. Shaping process conditions, as with themixing or compounding process conditions, may also result in undesirablepartitioning and/or cross-reactions. Therefore, control of any shapingprocess condition such as temperature, moisture content, shear rate andresidence time may be desirable to avoid partitioning and/orcross-reactions.

[0088] For example, a three layer structure comprising an annular matrixpolymer region and two barrier layers covering an interior and exteriorsurface, respectively, of the matrix polymer region may be formed bycoextruding the matrix polymer containing the bioactive agents andoptional radio-opacifying agent and/or therapeutic agent. In such acoextrusion process, the barrel and shaping die temperatures, screwspeed and compression ratio, may be controlled to prevent undesirablepartitioning and chemical modification of the bioactive agents. Forexample, coextrusion of a 19% vinyl acetate EVA copolymer as a matrixpolymer, compounded with 10% by weight triclosan, 10% by weightsalicylic acid and 30% by weight bismuth subcarbonate may be coextrudedwith two layers of a metallocene catalyzed polyethylene (“mPE”)copolymer such as an ethylene-octene copolymer (24% octene co-monomer)serving as barrier layers. In such a coextrusion process, a screw speedof 35 rpm on a 3:1 compression ratio, using a 1″ screw diameter with nomixing section and a barrel temperature of about 110° C. was found to besufficient to substantially prevent cross-reactions and bioactive agentpartitioning. As alluded to above, barrier layer materials may requirehigher processing temperatures during shaping than temperatures employedduring compounding of the matrix polymer and additives. Consequently, itmay be necessary to maintain portions of the extrusion apparatus athigher temperatures than employed during compounding. In thisembodiment, a barrel temperature of about 110° C. and a shaping headtemperature of about 150° C. are employed to facilitate formation of themPE copolymer barrier layers. While these temperatures are higher thanthe temperature (about 70° C.) used to compound the EVA matrix polymerand additives, substantial partitioning and chemical modification of thebioactive agents may, nonetheless, be avoided, due in part to the shortresidence time at these temperatures.

[0089] Other shaping processes, as mentioned above, include extrusioncoating and solvent coating. For example, a barrier layer polymer couldbe extruded onto a preformed matrix polymer region. This process isdistinguished from a coextrusion process in which the matrix polymer andbarrier layers are shaped substantially simultaneously. Alternatively, abarrier layer could be applied to a surface of a matrix polymer byapplying a solvent solution or liquid dispersion of a barrier polymeronto a surface of the matrix polymer followed by removing the solvent orliquid dispersing agent, e.g., by evaporation. Such a solution ordispersion of the barrier polymer may be applied by contacting a surfaceof the matrix polymer with the solution or dispersion by, for example,dipping or spraying. The use of these other shaping processes are notlimited to the application of a barrier layer to a matrix polymerregion. Therefore, a matrix polymer region may also be formed onto apreformed substrate by similar methods.

[0090] The medical device of the present invention may be anyimplantable or insertable medical device, particularly one that may besusceptible to microbial growth on and around the surfaces of thedevice, including attachment of microbes onto and the synthesis byattached microbes of biofilm on the surface of the medical device.Preferred implantable medical devices include those adapted to remainimplanted for a relatively long-term, i.e., for period of from about 30days to about 12 months or greater. However, devices intended to remainimplanted for about 30 days or less are also included within the scopeof the present invention.

[0091] Examples of implantable medical devices include, but are notlimited to, stents, stent grafts, stent covers, catheters, artificialheart valves and heart valve scaffolds, venous access devices, vena cavafilters, peritoneal access devices, and enteral feeding devices used inpercutaneous endoscopic gastronomy, prosthetic joints and artificialligaments and tendons. Preferred medical devices include those adaptedto bridge or provide drainage between two sterile areas of the body orbetween a sterile and non-sterile area of the body. Devices adapted tobridge or provide drainage between a sterile and a non-sterile area ofthe body are particularly susceptible to microbial growth, attachmentand biofilm formation due to contamination of the sterile area frommicrobes normally present in the non-sterile area. Medical devicesintended to be implanted in or bridge sterile body environments may besusceptible to microbial growth, attachment and biofilm formation, forexample, from microbial organisms that are ordinarily present in thenon-sterile area (i.e., non-pathogenic organisms), from those that arepresent due to disease, (i.e., pathogenic organisms) and from thoseintroduced during the insertion or implantation of the medical device.

[0092] Stents include biliary, urethral, ureteral, tracheal, coronary,gastrointestinal and esophageal stents. Preferred stents include biliarystents, ureteral stents and pancreatic stents. The stents may be of anyshape or configuration. The stents may comprise a hollow tubularstructure which is particularly useful in providing flow or drainagethrough biliary and ureteral lumens. Stents may also be coiled orpatterned as a braided or woven open network of fibers or filaments or,for example, as an interconnecting open network of articulable segments.Such stent designs may be more particularly suitable for maintaining thepatency of a body lumen such as a coronary artery. Thus, stents adaptedprimarily to provide drainage, in contrast to stents adapted primarilyto support a body lumen, will preferably have a continuous wallstructure in contrast to an open network wall structure.

[0093] Stent covers are also a preferred medical device of the presentinvention. For example, a stent cover may comprise a thin wall tubularor sheath-like structure adapted to be placed over a stent comprising anopen mesh stent of knitted, woven or braided design. A preferred stentcover is adapted to be placed over a biliary stent. The biliary stentcan be made of any material useful for such purpose including metallicand nonmetallic materials as well as shape memory materials. Amonguseful metallic materials include, but are not limited to, shape memoryalloys such as Nitinol®, and other metallic materials including, but notlimited to, stainless steel, tantalum, nickel-chrome, orcobalt-chromium, i.e., Elgiloy®. The biliary stent can be made from asingle strand or multiple strands of any such material and may beself-expanding. The stent cover may comprise a matrix polymer asdescribed herein which comprises an antimicrobial agent such astriclosan, a microbial attachment/biofilm synthesis inhibitor such assalicylic acid and a radio-opacifying agent such as bismuthsubcarbonate. A particularly preferred stent cover comprises anelastomeric polyurethane or polyurethane copolymer as described above.The stent cover is particularly advantageous in reducing tissue growththrough an open mesh stent while at the same time reducing microbialgrowth on and around the surface of the stent, reducing attachment ofmicrobes onto the stent, and reducing the synthesis of biofilm on thesurface of the stent.

[0094] Another preferred medical device of the present invention is apancreatic stent that provides drainage from the pancreas to theduodenom. Normally, the pancreas drains into the duodenum by thepancreatic duct. Implantable pancreatic drainage devices are sometimesdesired to alleviate problems such as strictures, sphincter stenoses,obstructing stones or to seal duct disruptions. However, when thepancreatic duct is opened, or an implantable medical device is placed inthe pancreas, morphological changes may occur that may lead topancreatitis.

[0095] It is believed that morphological changes in the pancreas uponinsertion of an implantable medical device may be related to the pHdifference between a normal pancreas and the duodenum into which thepancreas drains. The pancreas has a higher pH than the duodenum andexcretes aqueous bicarbonate to buffer the duodenum. The implantation ofa medical device into the pancreas may substantially reduce the abilityor effectiveness of the pancreas to provide this buffering action,potentially leading to undesirable morphological changes in thepancreas.

[0096] It is believed that by providing a pancreatic stent that releasesa buffering agent so as to create a pancreatic pH level in theenvironment of the implanted medical device, undesirable morphologicalchanges in the pancreas may be substantially reduced or even prevented.This may be accomplished by providing an agent in or on the surfaces ofa pancreatic stent such that when the pancreatic stent is exposed tophysiological fluids, the buffering agent is released from the stentcreating a locally higher pH environment around the device. Amongbuffering agents are included, but not limited to, bicarbonate saltssuch as sodium or potassium bicarbonate. Such buffering agents may beincorporated, for example, in a matrix polymer in a manner describedhereinabove with respect to bioactive agents, or they may be applied asa coating on a surface of a matrix polymer, or they may be applied in oras a coating on any optional barrier layer by any of the methodsdescribed above.

[0097] The invention will be further described with reference to thefollowing non-limiting Examples. It will be apparent to those skilled inthe art that many changes can be made in the embodiments described insuch Examples, consistent with the foregoing description, withoutdeparting from the scope of the present invention.

EXAMPLE 1

[0098] A single-layer matrix polymer structure is formed from a mixturecontaining an ethylene vinyl acetate (EVA) copolymer having a 19% vinylacetate content, 10% triclosan by weight of the mixture as anantimicrobial agent, 10% salicylic acid by weight of the mixture as amicrobial attachment/biofilm synthesis inhibitor, and 30% bismuthsubcarbonate by weight of the mixture as a radio-opacifying agent. Thebismuth subcarbonate is precompounded with the EVA copolymer (62.5%EVA/37.5% bismuth subcarbonate) and added to the triclosan and salicylicacid bioactive agents. Alternatively, the bismuth subcarbonate ispreblended with the triclosan and salicylic acid in a v-mixer withintensifier bar before adding to the polymer. A v-blender with anapproximately 13 rpm shell speed and a pin-type intensifier bar at about120 rpm for about 15 minutes produces a consistent, homogenous powderblend. The triclosan, salicylic acid and bismuth subcarbonate arecompounded with the EVA copolymer in an 18 mm screw diameter twin screwextruder with a low-shear profile screw design. The barrel temperaturein the screw is about 70° C. with a screw speed of about 200 rpm and athroughput of about 3.5 kg/hr. Since 70° C. is a relatively lowprocessing temperature for EVA, the triclosan acts as a plasticizer tofacilitate compounding and subsequent extrusion. After compounding, themixture is extruded into tubes in a standard 1″ screw diameter extruderwith a 24:1 L/D, 3:1 compression ratio, low shear screw. Maximum barreltemperature is about 100° C. to prevent reaction between the bismuthsubcarbonate and the salicylic acid. The screw speed is kept relativelylow, around 20 rpm, to keep the shear rate low and prevent excessviscous heat dissipation.

EXAMPLE 2

[0099] A three-layer structure is formed having a matrix polymer regionwith the same composition and compounding as described in Example 1, andcoextruded with barrier layers covering the inner and outer surfaces ofthe matrix polymer region. The barrier layers are formed of anethylene-octene copolymer in which the octane co-monomer content isabout 24%. Each of the barrier layers forms about 5% of the total wallthickness of the three-layer structure. Thicker or thinner barrierlayers may be provided to retard or increase the release rate of thebioactive agents from the matrix polymer. The compounded matrix polymerand barrier layers are coextruded while controlling the screw speed andtemperature to avoid overheating and undesirable cross-reactions and theconsequent chemical modification of the bioactive agents and/orradio-opacifying agent. The coextrusion is performed using a screw speedof about 35 rpm on a 3:1 compression ratio, a 1″ diameter screw with nomixing section. A barrel temperature of about 110° C. was found tosubstantially prevent cross-reactions. The copolymer barrier layersrequire higher processing temperatures at the shaping die at the head ofthe extruder. A shaping die temperature of about 150° C. was found toprovide adequate head pressure, layer quality and cross-reaction at theshaping die.

EXAMPLE 3

[0100] Approximately 2 cm lengths of extruded 19% vinyl acetate EVAcopolymer tubing containing varying amounts of triclosan (TCN),salicylic acid (SA) and bismuth subcarbonate (BsC) are incubated inphosphate buffered saline (PBS) at 37° C. for 0 (“no treatment”), 3, 8and 28 days. The purpose of incubation in PBS is to show longevity of SAinhibition on bacterial attachment after exposure, and release of SAfrom the extruded tube. After incubation in PBS, the tubes are exposed asolution containing approximately 10⁻⁴ to 10⁻⁵ cfu/ml e. coli for about4 hr at 37° C. with rotation at about 100 rpm. Subsequent to thisexposure, the samples are rinsed in saline and “rolled” following anestablished pattern onto a standard Mueller-Hinton agar plate. Theplates are incubated for about 18 to 24 hr to allow colonies to form.The colonies are counted and expressed as cfu per inch of tube.

[0101]FIG. 3 shows the normalized inhibitory response of the tubes. Theamounts of TCN, SA and BsC in the tubes are represented as % TCN/% SA/%BsC (wt % based on weight of vinyl acetate EVA copolymer). Therefore, atube having 10% TCN, 0% SA and 30% BsC is designated in FIG. 3 as“10/0/30”. FIG. 3 shows the inhibitory response of five tubes havingvarying weight percentages of TCN and SA and 30% BsC, normalized to a10/0/30 tube, given an inhibitory response value of 1. FIG. 3 shows thattubes containing 10% TCN and varying amounts (1%, 3% and 10% SA)inhibited bacterial attachment more effectively than tubes containingonly TCN (“10/0/30”) and inhibited bacterial attachment more effectivelythan tubes containing neither TCN nor SA (“0/0/30”). FIG. 3 also showsthat, as the amount of SA increased from 0% to 10%, with TCN constant at10%, the tubes were generally more effective at inhibiting bacterialattachment, suggesting that SA provides a synergistic effect. FIG. 3further shows that incubation of the tubes in PBS prior to exposure toe. coli did not significantly affect bacterial inhibition, suggestingthat effective amounts of TCN and SA remained in the extruded tubesafter extended incubation in PBS, i.e., that the bioactive agents werenot excessively or prematurely leached out of the extruded tubes. FIG. 4shows results (not normalized) for similar tubes incubated for 3 and 8days in PBS prior to exposure to e. coli.

EXAMPLE 4

[0102] Approximately 2 cm lengths of extruded 19% vinyl acetate EVAcopolymer tubing containing varying amounts of triclosan (TCN),salicylic acid (SA) and bismuth subcarbonate (BsC) are inserted into anagar lawn of either e. coli (FIG. 5) or staph (FIG. 6). The tubes arepositioned so as to extend vertically upwardly from the surface of theagar lawn (similar to birthday candles). After 24 hours in the agarlawn, the zone (diameter) of bacterial growth inhibition around thetubes is measured. The tubes are repositioned in fresh agar plates every24 hours, and the zone of bacterial growth inhibition is again measured.FIG. 5 shows the measurement results for the tubes positioned in theagar lawn of e. coli and FIG. 6 shows the results for the tubespositioned in the agar lawn of staph. FIGS. 5 and 6 show that the zoneof bacterial growth inhibition was larger as the percentage of TCNincreased from 0% to a maximum of 10%. A tube containing no TCN, butvarying amounts of SA did not effectively inhibit bacterial growth,suggesting that bacterial growth inhibition (as opposed to inhibition ofbacterial attachment) is predominantly provided by TCN. FIGS. 5 and 6also show that, for a given percentage of TCN, the measured zone ofbacterial growth inhibition is similar over a period extending to about40 days or longer, suggesting that the TCN component in the extrudedtubes effectively maintains its activity for extended periods of time.

[0103] The invention may be embodied in other specific forms withoutdeparting from its proper scope. The described embodiments and Examplesare to be considered in all respects only as illustrative and notrestrictive. The scope of the invention is, therefore, indicated by theappended claims rather than by the foregoing description. All changesthat come within the meaning and range of equivalency of the claims areto be embraced within their scope.

What is claimed is:
 1. An implantable medical device comprising (a) atleast one biocompatible matrix polymer region and (b) bioactive agentscomprising an antimicrobial agent and a microbial attachment/biofilmsynthesis inhibitor.
 2. The medical device of claim 1, wherein both theantimicrobial agent and microbial attachment/biofilm synthesis inhibitorare present in a single distinct matrix polymer region.
 3. The medicaldevice of claim 1, wherein the antimicrobial agent and the microbialattachment/biofilm synthesis inhibitor are present in distinct matrixpolymer regions.
 4. The medical device of claim 1, wherein saidantimicrobial agent is present in an amount effective to inhibit thegrowth of microbes on and around the device and the microbialattachment/biofilm synthesis inhibitor is present in an amount effectiveto inhibit the attachment of microbes onto and the synthesis andaccumulation of biofilm from attached microbes on the surface of thedevice.
 5. The medical device of claim 1, wherein said device is adaptedto remain implanted for a period of greater than about 30 days.
 6. Themedical device of claim 1, wherein said matrix polymer comprises abiocompatible biodegradable polymer.
 7. The medical device of claim 1,wherein said matrix polymer comprises a biocompatible non-biodegradablepolymer.
 8. The medical device of claim 7, wherein saidnon-biodegradable polymer is selected from the group consisting ofethylene vinyl acetate copolymers, copolymers of ethylene with acrylicacid or methacrylic acid, elastomeric polyurethanes and polyurethanecopolymers, metallocene catalyzed polyethylene, ionomers and vinylaromatic copolymers.
 9. The medical device of claim 6, wherein saidbiodegradable polymer is selected from the group consisting ofpolylactic acid, polyglycolic acid, copolymers and mixtures thereof. 10.The medical device of claim 8, wherein said non-biodegradable polymer isan ethylene vinyl acetate copolymer.
 11. The medical device of claim 10,wherein said ethylene vinyl acetate copolymer has a vinyl acetatecontent of from about 19% to about 28%.
 12. The medical device of claim10, wherein said ethylene vinyl acetate copolymer has a vinyl acetatecontent of from about 3% to about 15%.
 13. The medical device of claim1, wherein said antimicrobial agent is selected from the groupconsisting of triclosan and chlorhexidine and mixtures thereof.
 14. Themedical device of claim 13, wherein said antimicrobial agent istriclosan.
 15. The medical device of claim 14, wherein said microbialattachment/biofilm synthesis inhibitor is selected from the groupconsisting of NSAIDs, EDTA and EGTA.
 16. The medical device of claim 15,wherein said microbial attachment/biofilm synthesis inhibitor issalicylic acid or a salt or derivative thereof.
 17. The medical deviceof claim 16, wherein said microbial attachment/biofilm synthesisinhibitor is salicylic acid.
 18. The medical device of claim 4, whereinthe amount of said antimicrobial agent present in said matrix polymer isfrom about 0.5% to about 25% by weight of the matrix polymer.
 19. Themedical device of claim 4, wherein the amount of said microbialattachment/biofilm synthesis inhibitor present in said matrix polymer isfrom about 0.5% to about 25% by weight of the matrix polymer.
 20. Themedical device of claim 1, wherein said matrix polymer further comprisesa radio-opacifying agent.
 21. The medical device of claim 20, whereinsaid radio-opacifying agent comprises bismuth subcarbonate.
 22. Themedical device of claim 20 wherein the amount of said radio-opacifyingagent present in said matrix polymer is from about 0.5% to about 45% byweight of the matrix polymer.
 23. The medical device of claim 1, whereinthe matrix polymer further comprises at least one therapeutic agent. 24.The medical device of claim 23, wherein the therapeutic agent isselected from the group consisting of chemotherapeutic agents, NSAIDs,steroidal anti-inflammatory agents, and mixtures thereof.
 25. Themedical device of claim 23, wherein the therapeutic agent is selectedfrom the group consisting of cisplatin, methotrexate, doxorubicin,paclitaxel, docetaxel, dexamethasone, hydrocortisone and prednisone. 26.The medical device of claim 1, further comprising one or more barrierlayers at least partially covering said at least one matrix polymerregion.
 27. The medical device of claim 26, comprising a first matrixpolymer region; a first polymeric barrier layer at least partiallycovering an interior surface of said first matrix polymer region; and asecond polymeric barrier layer at least partially covering an exteriorsurface of said first matrix polymer region.
 28. The medical device ofclaim 27, wherein each of said first matrix polymer region, and saidfirst and second polymeric barrier layers is in the form of an annulus.29. The medical device of claim 28, wherein the first and secondpolymeric barrier layers comprise the same polymeric materials.
 30. Themedical device of claim 28, wherein the first and second polymericbarrier layers comprise different polymeric materials.
 31. The medicaldevice of claim 27, further comprising a second and, optionally, a thirdmatrix polymer region and a third and, optionally, a fourth polymericbarrier layer; wherein the second matrix polymer region is disposed onan outside surface of the second polymeric barrier layer and the thirdpolymeric barrier layer at least partially covers an exterior surface ofsaid second matrix polymer region; and, wherein the third matrix polymerregion, when present, is disposed on an interior surface of said firstpolymeric barrier layer and the fourth polymeric barrier layer at leastpartially covers an interior surface of said third matrix polymerregion.
 32. The medical device of claim 27, wherein the first matrixpolymer region comprises an ethylene vinyl acetate copolymer.
 33. Themedical device of claim 32, wherein each of the first and secondpolymeric barrier layers comprises a material selected from the groupconsisting of metallocene catalyzed polyethylenes and polyethylenecopolymers, ionomers, elastomeric polyurethanes and polyurethanecopolymers, ethylene vinyl acetate copolymers and copolymers of ethylenewith acrylic acid or methacrylic acid.
 34. The medical device of claim33, wherein the antimicrobial agent is selected from the groupconsisting of triclosan, chlorhexidine and combinations thereof, and themicrobial attachment/biofilm synthesis inhibitor is salicylic acid or asalt thereof.
 35. The medical device of claim 1, wherein the medicaldevice is selected from the group consisting of a stent cover, a biliarystent, a ureteral stent, a pancreatic stent, a urinary catheter, avenous access device, a peritoneal access device, a device connecting orproviding drainage between two sterile body environments, and a deviceconnecting or providing drainage between a non-sterile and a sterilebody environment.
 36. The medical device of claim 35, wherein the devicecomprises a device connecting or providing drainage between anon-sterile and a sterile body environment.
 37. The medical device ofclaim 36, wherein the device comprises a hollow tubular structure. 38.The medical device of claim 35, wherein the device comprises a stentcover.
 39. The medical device of claim 38, wherein said biocompatiblepolymeric matrix comprises polyurethane, said antimicrobial agentcomprises triclosan, said microbial attachment/biofilm synthesisinhibitor comprises salicylic acid or a salicylic acid derivative andfurther comprising a bismuth subcarbonate radio-opacifying agent. 40.The medical device of claim 38, wherein the stent cover comprises ahollow tubular structure adapted to be placed over a stent thatcomprises a woven, knitted or braided open mesh design comprising abiocompatible material.
 41. The medical device of claim 40, wherein thestent cover is placed over a biliary stent.
 42. The medical device ofclaim 40, wherein the biocompatible material is selected from the groupconsisting of stainless steel or a shape memory material.
 43. Themedical device of claim 35, wherein the medical device comprises apancreatic stent that provides drainage from the pancreas to theduodenum.
 44. The medical device of claim 43, wherein the pancreaticstent comprises a buffering agent.
 45. The medical device of claim 44,wherein said buffering agent, upon exposure to physiological fluids,creates a pancreas-compatible pH level in an environment in which thepancreatic stent is implanted.
 46. The medical device of claim 45,wherein said buffering agent is a bicarbonate salt.
 47. The medicaldevice of claim 46, wherein said bicarbonate salt is selected from thegroup consisting of sodium and potassium bicarbonate.
 48. A method ofmanufacturing an implantable or insertable medical device comprising:providing a combination of (a) one or more biocompatible matrix polymersand (b) bioactive agents comprising an antimicrobial agent and amicrobial attachment/biofilm synthesis inhibitor; processing saidcombination under conditions that substantially prevent preferentialpartitioning of any of said bioactive agents to a surface of any of saidbiocompatible matrix polymers and that substantially prevent chemicalmodification of said bioactive agents.
 49. The method of claim 48,further comprising controlling either or both of the temperature andmoisture content during said processing.
 50. The method of claim 48,wherein said processing comprises mixing said one or more biocompatiblematrix polymers with one or more of said bioactive agents to a form ahomogeneous mixture of said one or more matrix polymers and said one ormore bioactive agents.
 51. The method of claim 50, wherein saidhomogeneous mixture comprises both bioactive agents.
 52. The method ofclaim 50, wherein said mixing comprises applying mechanical shear tosaid one or more biocompatible matrix polymers and said one or morebioactive agents with a device selected from the group consisting of asingle screw extruder, a twin screw extruder, a banbury mixer, ahigh-speed mixer and a ross kettle.
 53. The method of claim 50, wheresaid mixing comprises forming a solvent solution or a liquid dispersionof said one or more bioactive agents and said one or more biocompatiblematrix polymers.
 54. The method of claim 50, further comprising shapingsaid homogenous mixture into a matrix polymer region of an implantableor insertable medical device.
 55. The method of claim 54, wherein saidshaping comprises a process selected from molding, calendaring, castingand solvent coating.
 56. The method of claim 54, wherein said shapingcomprises extrusion.
 57. The method of claim 56, wherein said extrusioncomprises forming at least one annular matrix polymer region.
 58. Themethod of claim 57, further comprising forming at least one polymericbarrier layer at least partially covering a surface of said annularmatrix polymer region.
 59. The method of claim 58, wherein said methodcomprises a process selected from extrusion coating said polymericbarrier layer onto said annular matrix polymer region and solventcoating said polymeric barrier layer onto said annular matrix polymerregion.
 60. The method of claim 58, wherein said covering comprisescoextruding said polymeric barrier layer and said annular matrix polymerregion.
 61. The method of claim 58, forming a first polymeric barrierlayer at least partially covering an interior surface of said annularmatrix polymer region and forming a second polymeric barrier layer atleast partially covering an exterior surface of said annular matrixpolymer region.
 62. The method of claim 61, wherein said coveringcomprises coextruding said first and second polymer barrier layers withsaid annular matrix polymer region.
 63. The method of claim 50, whereinsaid processing comprises forming homogeneous first and second mixturesof first and second biocompatible matrix polymers and one or more ofsaid bioactive agents and, optionally, forming a homogenous thirdmixture of a third biocompatible matrix polymer and one or more of saidbioactive agents.
 64. The method of claim 63, comprising coextrudingsaid homogenous first and second mixtures to form first and secondannular matrix polymer regions and, optionally, coextruding therewithsaid homogeneous third mixture to form a third annular matrix polymerregion.
 65. The method of claim 64, further comprising forming at leastfirst and second polymeric barrier layers at least partially coveringinterior and exterior surfaces of said first annular matrix polymerregion; forming a third polymer barrier layer at least partiallycovering an exterior surface of said second annular matrix polymerregion and, optionally, forming a fourth polymeric barrier layer atleast partially covering an interior surface of third annular matrixpolymer region.
 66. The method of claim 65, wherein said coveringcomprises coextruding said first, second and third polymeric barrierlayers with said first and second annular matrix polymer regions and,optionally, coextruding therewith said fourth polymeric barrier layerand said third annular matrix polymer region.
 67. The method of claim62, wherein said first annular matrix polymer region and said first andsecond barrier layers comprise a material selected from the groupconsisting of ethylene vinyl acetate copolymers, copolymers of ethylenewith acrylic acid or methacrylic acid, elastomeric polyurethanes andpolyurethane copolymers, metallocene catalyzed polyethylene andpolyethylene copolymers, ionomers, vinyl aromatic copolymers, siliconesand mixtures thereof.
 68. The method of claim 67, wherein said firstannular matrix polymer region comprises an ethylene vinyl acetatecopolymer having a vinyl acetate content of from about 19% to about 28%and said first and second polymeric barrier layers comprise ametallocene catalyzed polyethylene or polyethylene copolymer, or anionomer.
 69. The method of claim 68, wherein said first annular matrixpolymer region comprises salicylic acid or a salt thereof as saidmicrobial attachment/biofilm synthesis inhibitor, triclosan as saidantimicrobial agent and bismuth subcarbonate as a radio-opacifyingagent; and, said coextrusion is performed under conditions such thatsaid salicylic acid or salt thereof does not preferentially partition toa surface of said first annular matrix polymer region or to a surface ofsaid first or second polymeric barrier layers.
 70. The medical device ofclaim 26, wherein at least one of said one or more barrier layerscomprises a biodegradable polymer.
 71. The medical device of claim 70,where said biodegradable polymer is selected from the group consistingof polylactic acid, polyglycolic acid and copolymers and mixturesthereof.
 72. An implantable or insertable medical device comprising atleast one biocompatible matrix polymer region comprising a materialselected from the group consisting of ethylene vinyl acetate copolymers,copolymers of ethylene with acrylic acid or methacrylic acid,metallocene catalyzed polyethylenes and polyethylene copolymers,ionomers, vinyl aromatic copolymers, elastomeric polyurethanes andpolyurethane copolymers, silicones and mixtures thereof; bioactiveagents comprising an antimicrobial agent selected from the groupconsisting of triclosan, chlorhexidine and mixtures thereof; a microbialattachment/biofilm synthesis inhibitor selected from the groupconsisting of salicylic acid and salts and derivatives thereof, and, aradio-opacifying agent selected from the group consisting of bismuthsubcarbonate, bismuth oxychloride, bismuth trioxide, barium sulfate,tungsten and mixtures thereof.